when hyperglycemia strikes pregnancy: criteria for diagnosis

WHEN HYPERGLYCEMIA STRIKES PREGNANCY:CRITERIA FOR DIAGNOSIS

Iris Thiele Isip Tan MD, MSc, FPCP, FPSEMClinical Associate Professor, UP College of Medicine

Section of Endocrinology, Diabetes & MetabolismDepartment of Medicine, Philippine General Hospital

Tuesday, November 8, 11

Hyperglycemia Adverse Pregnancy Outcomes (HAPO)

International Association of Diabetes

in Pregnancy Study Groups (IADPSG)

UNITE for Diabetes CPG on screening & diagnosis of GDM


Hyperglycemia Adverse Pregnancy Outcomes HAPO


HAPO

http://www.flickr.com/photos/mikewade/3267336862/

BW>90th %ile

Primary CS

Cord blood serum C-peptide >90 %ile

23,316 pregnant

15 centers9 countries

Neonatal hypoglycemia

http://www.flickr.com/photos/tessawatson/379265818/

75-g OGTT 24-32 wks

AOG

http://www.flickr.com/photos/clairity/1385780317/http://www.flickr.com/photos/j2dread/4501366303/

NEJM 2008; 358:1991-2002






http://www.flickr.com/photos/clairity/1385780317/


http://www.flickr.com/photos/j2dread/4501366303/


OR for adverse pregnancy outcomes

1 level SD increase

FPG 6.9 mg/dL (0.4 mmol/L)

HAPO NEJM 2008; 358:1991-2002

1 h PG 30.9 mg/dL (1.7 mmol/L)2 h PG 23.5 mg/dL (1.3 mmol/L)


HAPO


BW>90th %ile

Fasting 1.38

(95%CI 1.32,1.44)OR for adverse

pregnancy outcomes

NEJM 2008; 358:1991-2002

1h PG 1.46

(95%CI 1.39,1.53)

2h PG 1.38

(95%CI 1.32,1.44)




HAPO

Fasting 1.55


pregnancy outcomes

NEJM 2008; 358:1991-2002

1h PG 1.46

(95%CI 1.38,1.54)

2h PG 1.37

(95%CI 1.30,1.44)

Cord blood serum C-peptide >90 %ile





HAPO

Fasting 1.11


pregnancy outcomes

NEJM 2008; 358:1991-2002

1h PG 1.10

(95%CI 1.06,1.15)

2h PG 1.08

(95%CI 1.03,1.12)

Primary CS





HAPO

Fasting 1.08


pregnancy outcomes

NEJM 2008; 358:1991-2002

1h PG 1.13

(95%CI 1.03,1.26)

2h PG 1.10

(95%CI 1.00,1.12)

Neonatal hypoglycemia





HAPO NEJM 2008; 358:1991-2002

No obvious threshold at which risks increased


HAPO NEJM 2008; 358:1991-2002

FPG mg/dLCategory 1 <752 75-793 80-844 85-89 5 90-946 95-997 >100

FPG mg/dLCategory 1 <752 75-793 80-844 85-89 5 90-946 95-997 >100



HAPO NEJM 2008; 358:1991-2002

1h PG mg/dLCategory 1 <1052 106-1323 133-1554 156-171 5 172-1936 194-2117 >212

1h PG mg/dLCategory 1 <1052 106-1323 133-1554 156-171 5 172-1936 194-2117 >212



HAPO NEJM 2008; 358:1991-2002

2h PG mg/dLCategory1 <902 91-1083 109-1254 126-1395 140-1576 158-1777 >178

2h PG mg/dLCategory1 <902 91-1083 109-1254 126-1395 140-1576 158-1777 >178



HAPO NEJM 2008; 358:1991-2002

Macrosomia

Hypoglycemia

C-section

C-peptide


Coustan et al. AJOG 2010; 202(6):654.e1-654.e6

“... the relationship between maternal glucose levels and fetal growth and outcome appear to be a basic biologic phenomenon, and not a clearly demarcated disease state ...”


International Association of Diabetes in Pregnancy Study Groups IADPSG


http://www.sxc.hu/photo/358002

IADPSGencourage and facilitate research and advance education

facilitate an international approach to enhancing the quality of care for women with diabetes in pregnancy






workshop/conference June 2008 (220 delegates approx 40 countries)

consensus development session (50 delegates)

IADPSG


OR for increased neonatal body fat, LGA and cord serum C-peptide

Mean glucose as reference


OR%

Subjects > Threshold

Positive Predictive Valuefor >90th %ile

Positive Predictive Valuefor >90th %ile

Positive Predictive Valuefor >90th %ileOR

% Subjects > Threshold Birth

weight C-peptide % Body fat

1.75 16.1 16.2 17.5 16.62.0 8.8 17.6 19.7 18.8



IADPSG recommendation for diagnosis of GDM

FBS 92 mg/dL

1h 180 mg/dL

2h 153 mg/dL

Diagnosis requires only one threshold value exceeded




FBS 92 mg/dL

1h 180 mg/dL

2h 153 mg/dL

ADA FBS 95 mg/dL1h 180 mg/dL2h 155 mg/dL

Diagnosis requires only one threshold value exceeded


First prenatal visit Measure FPG, A1c or random plasma glucose in all or only in high-risk

IADPSG Consensus Panel. Diabetes Care Mar 2010;33(3):676-82

Overt Diabetes in Pregnancy

FPG > 7 mmol/L A1c > 6.5%Random PG > 11.1 mmol/L

Gestational Diabetes

FPG 5.1-6.9 mmol/L (92-125 mg/dL)

Order a 75-g OGTT at 24-28 wks AOG

FPG <5.1 mmol/L




FBS 92 mg/dL

1h 180 mg/dL

2h 153 mg/dLDiagnosis requires only one

threshold value exceeded

Overt diabetesFPG >7.0 mmol/L (126 mg/dL)

24-28 wks AOG


http://www.flickr.com/photos/kkoshy/4334413228/

More women will be diagnosed with GDM17.8% of pregnant women

Use of IADPSG criteria

Ryan EA. Diabetologia 2011; 54:480-6




Using HAPO data

+ 1,702 women with GDMof 23,316 pregnancies

Nurses, dietitians & physicians

Glucose monitoringTherapy of diabetes



Diagnosis of GDM identifies women at risk of type 2 diabetes

IADPSG criteria may overestimate

high rates of diabetes in women

with GDM history



X 140 cases of LGAX 21 cases of shoulder dystocia

X 16 cases of birth injury






X 140 cases of LGAX 21 cases of shoulder dystocia

X 16 cases of birth injury


Modest outcomes?




78% of LGA born to undiagnosed womenFBS

92 mg/dL

BW>90th %ile

1h 180 mg/dL

2h 153 mg/dL

X Ryan EA. Diabetologia 2011; 54:480-6


Gestational diabetes would be diagnosed if one or morevalues met or exceeded the following levels of glucose:fasting 5.1 mmol/l, 1 h post glucose 10.0 mmol/l and 2 hpost glucose 8.5 mmol/l. Use of these criteria will result in17.8% of the pregnant population being diagnosed withgestational diabetes. A detailed analysis of the same HAPOstudy information and other recent related publicationsraises issues that are worthy of further debate in the widerdiabetes community.

Observational data

HAPO was an international prospective observational studyof 23,316 pregnant women directed to answer the question:‘Is hyperglycaemia during pregnancy, at a level below thatfor overt diabetes, associated with increased risk ofmaternal or fetal complications?’ [2]. The participatingwomen had an OGTT and were divided into seven glucosecategories. The category 3 group encompassed the meanglucose values, i.e. fasting 4.5 mmol/l, 1 h post OGTT7.4 mmol/l and 2 h post OGTT 6.2 mmol/l, while the newproposed cut-offs from IADPSG fall in category 5. Theprimary endpoints were large-for-gestational age infants(LGA), primary Caesarean section rate, neonatal hypogly-caemia and cord C-peptide. The study demonstrated acontinuous relationship between glycaemia (fasting, and 1or 2 h post glucose load) and each of the primary outcomes,having adjusted for field centre and ethnicity. Whilesupporting the Pedersen hypothesis [3], the results did notshow any inflection point indicating clearly increased riskof any of these outcomes with a particular glucose category;rather, risk increased gradually over the glucose range.

A further publication from the group examined the roleof maternal BMI with the same primary outcomes [4]. Thisreport used an adjustment (Model 1) for many of theexpected confounders (age, alcohol, smoking, sex etc.), andalso a model (Model 2) that adjusted for fasting plasma

glucose and mean arterial pressure. The OR for LGA,primary Caesarean section and cord C-peptide increasedsignificantly for increasing categories of BMI, this differ-ence being maintained when adjusted for glucose and meanarterial pressure (reference group BMI <22.6 kg/m2;Fig. 1a). When the plot for LGA vs glucose is added(reference group category 1 glucose as used in the HAPOreport; Fig. 1a), it is apparent that maternal BMI has agreater impact on OR than maternal glucose in all exceptthe highest glucose category. This is also true for theprimary Caesarean section rate (Electronic supplementarymaterial [ESM] Fig. 1a), whereas the glucose level hadmore influence on the OR for cord C-peptide in glucosecategories 5–7 (ESM Fig. 1b). Thus, maternal BMI andglucose both contribute to risk of LGA, but the role of BMIwas more pronounced than that of glucose in determiningLGA incidence, until the highest glucose category wasreached. Using the category BMI 22.6–28.4 kg/m2 (whichincludes overweight women) and category 3 for glucose asthe reference groups (i.e. using reference groups thatinclude the means) shows that BMI and glucose have asimilar impact on the OR (ESM Fig. 2a–c).

The majority of women from the HAPO data hadglucose levels !category 3, i.e. the category encompassingthe mean glucose level (Fig. 1b). Moreover, the number ofLGA increased proportionately with higher glucose levels(Fig. 1b), but when the numbers of mothers with LGA ingiven glucose categories are classed separately (Fig. 1c),the majority (63%) of women with LGA are seen to haveglucose levels from the OGTT at or lower than category 3,the category incorporating the mean glucose level. This isalso true for the 1 and 2 h post-load challenge (ESMFig. 3). It is also noteworthy that at category 5 (equivalentto the IADPSG cut-off criteria, accepting that some cases incategory 5 will lie above these cut-offs within category 5)women below these cut-offs who had LGA represented78% of all women giving birth to LGA.

BMI category (Kg/m2)

Glucose category

Wom

en (

n)

Wom

en (

n)

8,000 700

600

500

400

300

200

100

0

6,000

4,000

2,000

0

<22.6 22.6!28.4

28.5!32.9

33.0!37.4

37.5! 42.041.9

1 2 3 4 5 6 7

Glucose category1 2 3 4 5 6 7

a b c

OR

0

1

2

3

4

5

1 3 52 4 6 7Glucose category

Fig. 1 a Relationship of the OR for an infant of birthweight >90thpercentile vs the BMI in categories (reference group BMI <22.6 kg/m2

[4]) or maternal fasting glucose in categories from HAPO (diamonds;reference group category 1 lowest glucose [2]). a The BMIrelationship is adjusted for model 1 (circles) or model 2 (triangles)

(see text for details). The relationship for maternal fasting glucosecategories is also shown (black diamonds). b Number of participantsin each category of glucose in HAPO (white bars), with number ofmothers with LGA infants (black bars). c Number of participants ineach category of glucose who had LGA infants

Diabetologia (2011) 54:480–486 481


Greater impact of maternal BMI on OR for LGA than maternal glucose except highest glucose category

HAPO

● BMI Model 1▲ BMI Model 2

◆ Maternal FG

Model 1: Adjusted for age, alcohol, smoking, sex, etc.Model 2: Adjusted for mean FG and MAP


Gestational diabetes would be diagnosed if one or morevalues met or exceeded the following levels of glucose:fasting 5.1 mmol/l, 1 h post glucose 10.0 mmol/l and 2 hpost glucose 8.5 mmol/l. Use of these criteria will result in17.8% of the pregnant population being diagnosed withgestational diabetes. A detailed analysis of the same HAPOstudy information and other recent related publicationsraises issues that are worthy of further debate in the widerdiabetes community.

Observational data

HAPO was an international prospective observational studyof 23,316 pregnant women directed to answer the question:‘Is hyperglycaemia during pregnancy, at a level below thatfor overt diabetes, associated with increased risk ofmaternal or fetal complications?’ [2]. The participatingwomen had an OGTT and were divided into seven glucosecategories. The category 3 group encompassed the meanglucose values, i.e. fasting 4.5 mmol/l, 1 h post OGTT7.4 mmol/l and 2 h post OGTT 6.2 mmol/l, while the newproposed cut-offs from IADPSG fall in category 5. Theprimary endpoints were large-for-gestational age infants(LGA), primary Caesarean section rate, neonatal hypogly-caemia and cord C-peptide. The study demonstrated acontinuous relationship between glycaemia (fasting, and 1or 2 h post glucose load) and each of the primary outcomes,having adjusted for field centre and ethnicity. Whilesupporting the Pedersen hypothesis [3], the results did notshow any inflection point indicating clearly increased riskof any of these outcomes with a particular glucose category;rather, risk increased gradually over the glucose range.

A further publication from the group examined the roleof maternal BMI with the same primary outcomes [4]. Thisreport used an adjustment (Model 1) for many of theexpected confounders (age, alcohol, smoking, sex etc.), andalso a model (Model 2) that adjusted for fasting plasma

glucose and mean arterial pressure. The OR for LGA,primary Caesarean section and cord C-peptide increasedsignificantly for increasing categories of BMI, this differ-ence being maintained when adjusted for glucose and meanarterial pressure (reference group BMI <22.6 kg/m2;Fig. 1a). When the plot for LGA vs glucose is added(reference group category 1 glucose as used in the HAPOreport; Fig. 1a), it is apparent that maternal BMI has agreater impact on OR than maternal glucose in all exceptthe highest glucose category. This is also true for theprimary Caesarean section rate (Electronic supplementarymaterial [ESM] Fig. 1a), whereas the glucose level hadmore influence on the OR for cord C-peptide in glucosecategories 5–7 (ESM Fig. 1b). Thus, maternal BMI andglucose both contribute to risk of LGA, but the role of BMIwas more pronounced than that of glucose in determiningLGA incidence, until the highest glucose category wasreached. Using the category BMI 22.6–28.4 kg/m2 (whichincludes overweight women) and category 3 for glucose asthe reference groups (i.e. using reference groups thatinclude the means) shows that BMI and glucose have asimilar impact on the OR (ESM Fig. 2a–c).

The majority of women from the HAPO data hadglucose levels !category 3, i.e. the category encompassingthe mean glucose level (Fig. 1b). Moreover, the number ofLGA increased proportionately with higher glucose levels(Fig. 1b), but when the numbers of mothers with LGA ingiven glucose categories are classed separately (Fig. 1c),the majority (63%) of women with LGA are seen to haveglucose levels from the OGTT at or lower than category 3,the category incorporating the mean glucose level. This isalso true for the 1 and 2 h post-load challenge (ESMFig. 3). It is also noteworthy that at category 5 (equivalentto the IADPSG cut-off criteria, accepting that some cases incategory 5 will lie above these cut-offs within category 5)women below these cut-offs who had LGA represented78% of all women giving birth to LGA.

BMI category (Kg/m2)

Glucose category

Wom

en (

n)

Wom

en (

n)

8,000 700

600

500

400

300

200

100

0

6,000

4,000

2,000

0

<22.6 22.6!28.4

28.5!32.9

33.0!37.4

37.5! 42.041.9

1 2 3 4 5 6 7

Glucose category1 2 3 4 5 6 7

a b c

OR

0

1

2

3

4

5

1 3 52 4 6 7Glucose category

Fig. 1 a Relationship of the OR for an infant of birthweight >90thpercentile vs the BMI in categories (reference group BMI <22.6 kg/m2

[4]) or maternal fasting glucose in categories from HAPO (diamonds;reference group category 1 lowest glucose [2]). a The BMIrelationship is adjusted for model 1 (circles) or model 2 (triangles)

(see text for details). The relationship for maternal fasting glucosecategories is also shown (black diamonds). b Number of participantsin each category of glucose in HAPO (white bars), with number ofmothers with LGA infants (black bars). c Number of participants ineach category of glucose who had LGA infants

Diabetologia (2011) 54:480–486 481


HAPO☐ Participants■ Participants with LGA infants

Majority of women had glucose levels < Cat. 3 (mean glucose level)

Most cases of LGA occur in normal maternal glycemia


Proposed IADPSG diagnostic criteria are based on LGA, cord-C peptide and fetal adiposity.

Treatment reduces perinatal morbidityACHOIS

Crowther et al. NEJM 2005; 352:2477-86.

Landon et al NEJM 2009; 361:1339-48.


ACHOISCrowther et al. NEJM 2005; 352:2477-86.

Crowther CA et al. Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes. NEJM 2005; 352:2477-86.

PI

MO

GDM24-28 wks AOG

Intervention (n=490)

diet CBG insulin vs

routine care (n=510)

Serious perinatal

complications death

shoulder dystociabone fracturenerve palsy

Randomized controlled

trial


ACHOISCrowther et al. NEJM 2005; 352:2477-86.

Crowther CA et al. Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes. NEJM 2005; 352:2477-86.

PI

MO

GDM24-28 wks AOG


diet CBG insulin vs


Serious perinatal

complications death

shoulder dystociabone fracturenerve palsy


trial

Any serious perinatal complication Adj RR 0.33 (95% CI 0.14-0.75), p=0.01


Landon et al NEJM 2009; 361:1339-48.

PI

MO


diet CBG insulin vs


Composite of stillbirth/perinatal

death and neonatal

complications


trial

“mild” GDM24-31 wks AOG

Landon MB et al. A multicenter, randomized trial of treatment for mild gestational diabetes. NEJM 2009; 361:1339-48.

hyperbilirubinemia hypoglycemia

hyperinsulinemia birth trauma


Landon et al NEJM 2009; 361:1339-48.

PI

MO


diet CBG insulin vs


Composite of stillbirth/perinatal

death and neonatal

complications


trial



hyperbilirubinemia hypoglycemia

hyperinsulinemia birth trauma

Composite endpoint RR 0.87 (95% CI 0.72-1.07), p=0.14


Landon et al NEJM 2009; 361:1339-48.

PI

MO


diet CBG insulin vs



trial





Landon et al NEJM 2009; 361:1339-48.

PI

MO


diet CBG insulin vs



trial




LGA infants RR 0.49

(95%CI 0.32-0.76) p<0.001

BW >4000 g RR 0.41

(95%CI 0.26-0.66) p<0.001


http://www.flickr.com/photos/craigoneal/4084388198/

OGTT is poorly reproducibleDiagnosis based on a single test, on a single abnormal value






HAPO data collected at 24-28 wks AOG

Fasting glucose 5.1 mmol/L at 7 wks AOG = GDM



IADPSGACOG recommends against IADPSG consensus

1.All pregnant women should be screened for GDM by patient history, clinical risk factors or a 50-g, 1-hour loading test to determine blood glucose levels.

ACOG Committee on Obstetric Practice. Screening & Diagnosis of Gestational Diabetes Mellitus. Obstetrics & Gynecology 2011; 118(3):751-3






2.The diagnosis of GDM can be made based on the result of the 100-g, 3h OGTT.

Carpenter & Coustan or NDDG criteria







3.Diagnosis of GDM based on the 1-step screening and diagnosis test outlined in the IADPSG guidelines is not recommended at this time because there is no evidence that diagnosis using these criteria leads to clinically significant improvement in maternal or newborn outcomes, and it would lead to a significant increase in healthcare costs.





UNITE for Diabetes CPG on screening &

diagnosis of GDM


Should universal screening for diabetes be done among pregnant women?

Recommendation:

All pregnant women should be screened for gestational diabetes (Level 2, Grade B).

6.1


For pregnant women, when should screening be done?

Recommendations:1. All pregnant women should be evaluated at the first prenatal visit for risk factors for diabetes (Level 4, Grade C).

6.2


Risk Factors for Gestational Diabetes

Prior history of GDM (OR 23.6 [95%CI 11.6, 48.0])3

Glucosuria (OR 9.04 [95%CI 2.6, 63.7]2; PPV 50% 4)

Family history of diabetes (OR 7.1 [95%CI 5.6, 8.9]1; OR 2.74 [95%CI 1.47, 5.11]3)

First-degree relative with type 2 diabetes (PPV 6.7%)4

First-degree relative with type 1 diabetes (PPV 15%)4Prior macrosomic baby (OR 5.59 [95%CI 2.68, 11.7])3

Age >25 years old (OR 1.9 [95%CI 1.3, 2.7]1; OR 3.37 [95%CI 1.45, 7.85]3)

! !1 Davey RX, Hamblin PS. Selective versus universal screening for gestational diabetes mellitus:

an evaluation of predictive risk factors. Medical Journal of Australia 2001;174(3):118–21.

2 Schytte T, Jorgensen LG, Brandslund I, et al. The clinical impact of screening for gestational diabetes. Clinical Chemistry and Laboratory Medicine 2004;42(9):1036–42.

3 Ostlund I, Hanson U. Occurrence of gestational diabetes mellitus and the value of different screening indicators for the oral glucose tolerance test. Acta Obstetricia et Gynecologica Scandinavica 2003;82(2):103–8.

4 Griffin ME, Coffey M, Johnson H, et al. Universal vs. risk factor-based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and outcome. Diabetic Medicine 2000;17(1):26–32.


Risk Factors for Gestational Diabetes

Diagnosis of polycystic ovary syndrome (OR 2.89 [95%CI 1.68, 4.98])5

Overweight or obese before pregnancy

(BMI >27 kg/m2 OR 2.3 [95%CI 1.6, 3.3]1; BMI>30 kg/m2 OR 2.65 [95%CI 1.36, 5.14]3

Macrosomia in current pregnancy (PPV 40% 4)Polyhydramnios in current pregancy (PPV 40% 4)Intake of drugs affecting carbohydrate metabolism

3 Ostlund I, Hanson U. Occurrence of gestational diabetes mellitus and the value of different screening indicators for the oral glucose tolerance test. Acta Obstetricia et Gynecologica Scandinavica 2003;82(2):103–8.

1 Davey RX, Hamblin PS. Selective versus universal screening for gestational diabetes mellitus: an evaluation of predictive risk factors. Medical Journal of Australia 2001;174(3):118–21.

4 Griffin ME, Coffey M, Johnson H, et al. Universal vs. risk factor-based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and outcome. Diabetic Medicine 2000;17(1):26–32.

5 Toulis KA, Goulis DG, Kolibiankis EM, Venetis CA, et al. Risk of gestational diabetes mellitus in women with polycystic ovary syndrome: a systematic review and a meta-analysis. Fertil Steril 2009;92(2):667–77.



Recommendations:2. High-risk women should be tested at the soonest possible time (Level 3, Grade B).

6.2



Recommendations:3. Routine testing for gestational diabetes is recommended at 24-28 weeks age of gestation for women with no risk factors (Level 3, Grade B).

6.2



Recommendations:4. Testing for gestational diabetes should still be carried out in women at risk, even beyond 24 to 28 weeks age of gestation (Level 3, Grade C).

6.2


Which tests should be used to screen pregnant women for gestational diabetes?

Recommendation:An oral glucose tolerance test (OGTT), preferably the 75-g OGTT, should be used to screen for gestational diabetes (Level 3, Grade B).

6.3


What criteria will be used to interpret the 75-g OGTT?

Recommendation:

The criteria put forth by the International Association of Diabetes & Pregnancy Study Groups (IADPSG) will be used to interpret the 75-g OGTT (Level 3, Grade B).

6.4

International Association of Diabetes and Pregnancy Study Groups Consensus Panel. IADPSG Recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy. Diabetes Care 2010; 33(3):676-82.


Hyperglycemia Adverse Pregnancy Outcomes (HAPO)

International Association of Diabetes

in Pregnancy Study Groups (IADPSG)

UNITE for Diabetes CPG on screening & diagnosis of GDM


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when hyperglycemia strikes pregnancy: criteria for diagnosis

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